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Search: Loss[Title] AND myogenic[Title] AND potential[Title] AND fusion[Title] AND capacity[Title] AND muscle[Title] AND stem[Title] AND cells[Title] AND isolated[Title] AND contractured[Title] AND muscle[Title] AND children[Title] AND cerebral[Title] AND palsy[Title]

Department of Orthopaedic Surgery, University of California, San Diego, La Jolla, California.

4

Bioengineering Department, University of California, San Diego, La Jolla, California.

5

ACEA Biosciences Incorporated, San Diego, California.

6

Children's Hospital and Health Center , San Diego, California.

Abstract

Cerebralpalsy (CP) is the most common cause of pediatric neurodevelopmental and physical disability in the United States. It is defined as a group of motor disorders caused by a nonprogressive perinatal insult to the brain. Although the brain lesion is nonprogressive, there is a progressive, lifelong impact on skeletal muscles, which are shorter, spastic, and may develop debilitating contractures. Satellite cells are resident musclestemcells that are indispensable for postnatal growth and regeneration of skeletal muscles. Here we measured the myogenicpotential of satellite cellsisolated from contractured muscles in children with CP. When compared with typically developing (TD) children, satellite cell-derived myoblasts from CP differentiated more slowly (slope: 0.013 (SD 0.013) CP vs. 0.091 (SD 0.024) TD over 24 h, P < 0.001) and fused less (fusion index: 21.3 (SD 8.6) CP vs. 81.3 (SD 7.7) TD after 48 h, P < 0.001) after exposure to low-serum conditions that stimulated myotube formation. This impairment was associated with downregulation of several markers important for myoblast fusion and myotube formation, including DNA methylation-dependent inhibition of promyogenic integrin-β 1D (ITGB1D) protein expression levels (-50% at 42 h), and ~25% loss of integrin-mediated focal adhesion kinase phosphorylation. The cytidine analog 5-Azacytidine (5-AZA), a demethylating agent, restored ITGB1D levels and promoted myogenesis in CP cultures. Our data demonstrate that muscle contractures in CP are associated with loss of satellite cell myogenicpotential that is dependent on DNA methylation patterns affecting expression of genetic programs associated with musclestem cell differentiation and muscle fiber formation.